Insulin use in Type 2 Diabetes

Transcription

1 Insulin use in Type 2 Diabetes 1

2 Conflict of Interest I have been on advisory boards or had speaker fees from the following pharmaceutical companies: - Eli Lilly - Novo Nordisk - Sanofi Aventis - MSD - Astra Zeneca I have been on the New Zealand Guideline Group for Diabetes and past member of PTAC Diabetes subcommittee for Pharmac. 2

3 Other Conflicts of Interest Work vs leisure balance When to retire? Continue to support the Blues Rugby Team or move to Hamilton 3

4 The Diabetes Burden Prevalence and incidence of T2 Diabetes increasing in conjunction with: - obesity rates - westernisation of lifestyles - Ageing - Ethnicity Up to 12% of health budget. Inzucchi SE et al. Diabetes Care : Leading cause of: - Cardiovascular disease - Blindness - End stage renal failure - Amputations - Hospitalisations Associated with risk of: - Cancer - Psychiatric illness - Cognitive decline - Chronic liver disease - Accelerated arthritis 4

5 SORTING OUT A TARGET What does the evidence say? 5

6 Relationship of Glycaemia Control to Outcome UKPDS: Newly diagnosed Type 2 For every 1% decrease in HbA1c there was a - 37% risk reduction in microvascular complaints - 21% risk reduction in diabetes-related death - 14% risk reduction in myocardial infarct Metformin had 40-50% in mortality, and M.I. despite only 0.6% difference in HbA1c 6

7 Relationship of Glycaemia Control to Outcome 10 YEARS AFTER UKPDS: Despite now similar HbA1c between two groups Benefits maintained including CVD rates and mortality, i.e. EARLY maintenance of glycaemic control matters. N Engl J Med 2008; 359:

8 Relationship of Glycaemia Control to Outcome 2008 ACCORD / ADVANCE / VADT studies: Compared two levels of glycaemic control on C.V. end points in middle-aged/older patients with well established T2DM at high C.V. risk. Aim HbA1c < 6% or <6.5%. No benefit in driving HbA1c to less than 6.5% (42mmol/mol) and Accord showed 22% mortality in so doing. Probable 15% risk reduction in non-fatal M.I. for 1% decrease in HbA1c but no benefits in all cause mortality for this group. N Engl J Med 2009, 360:

9 Relationship of Glycaemia Control to Outcome Conclusion: Very tight control in people with very high C.V. risk with long standing T2 diabetes not justified unless easily done with diet/metformin. HbA1c target needs to be individualised from up to 65 mmol/mol. 9

10 Glycaemic Targets Individualise, e.g. 1. HbA1c mmol/mol - Short disease duration - Long life expectation - No significant C.V.D. - Achievable without significant hypoglycaemia with simple regimens 2. HbA1c mmol/mol - Limited life expectancy - Advanced complications - Extensive co-morbidities - Lower targets extremely difficult despite best efforts - History of severe hypoglycaemia 10

11 Glycaemic Targets SMBG - Fasting < 7mmol/L - Postprandial <10mmol/L ideal 11

12 Patient-Centred Approach Providing care that is respectful of and responsive to individual patient preferences, needs and values and ensuring that patient values guide all clinical decisions. Engaging patients in health care decisions may enhance adherence to therapy. BMA Science & Education. January

13 In T2 Diabetes Insulin resistance Abnormal islet cell function progressive loss of ß cells (glucolipotoxicity) and ß cells function. Abnormalities in incretin system especially GLP-I which influences insulin and glucagon secretion, gastric emptying and appetite. All may be reversible with weight loss. 13

14 ß-Cell Volume Reduced 40% in Patients with IFG and up to 60% in Patients with T2D 14

15 Contribution of FBG and PPBG to Overall Diurnal Hyperglycaemia 15

16 Principles of Management Prior to Medication Lifestyle: Personalised diet advice vs groups 5-10% weight loss is helpful. Realism. Exercise ideal 150 min / week but any increase is good Use for 3 months before medication if likely to be successful Weight loss hard to sustain 16

17 Oral Agents Metformin is drug of choice 10% G.I. side effects take with/after food Titrate to 2.5gms / day use B.D. to aid compliance Can use if egfr >30ml/min Benefits in terms of C.V. Disease?? Cancer 17

18 Other Oral Drugs 1. Sulphonylureas - Cheap - B.D. - Risk of hypoglycaemia esp in elderly - May increase rate of ß cell failure 18

19 Other Oral Drugs or 1. Sulphonylureas - Cheap - B.D. - Risk of hypoglycaemia esp in elderly - May increase rate of ß cell failure 2. TZDs (Pioglitazone) - Reduce insulin resistance - Once daily - Helps fatty liver - But weight gain; oedema; bones density and fractures; heart failure if at risk 19

20 or or Other Oral Drugs 1. Sulphonylureas - Cheap - B.D. - Risk of hypoglycaemia esp in elderly - May increase rate of ß cell failure 2. TZDs (Pioglitazone) - Reduce insulin resistance - Once daily - Helps fatty liver - But weight gain; oedema; bones density and fractures; heart failure if at risk 3. DPP4 Inhibitors (e.g. Sitagliptin) - Hypoglycaemia not significantly different vs placebo used singly or in combination with metformin*. - Weight neutral - Funding currently under Pharmac review *Goldstein BJ et al. Diabetes Care (8):

21 Consider Acarbose - Mild - G.I. side effects Injectable GLP agonist (e.g. Exanatide* / Liraglutide) - Glucose lowering (with secondary weight loss effect) - Instead of insulin? - Potentially big future *Exenatide is indicated as add on tx to metformin, or sulphonylurea or a combination of both where glycaemic control has not been achieved. 21

22 Consider BARIATRIC SURGERY if BMI > 35 and duration of diabetes less than 10 years 22

23 Even consider intermittent modified VL Calorie Diet, e.g. Optifast for 8-10 weeks. May improve ß cell function and medication dependency Taylor et al Lancet

24 And or Crucial Importance Always attack other C.V. risk factors Assess risk and where appropriate: - Statin to LDL to < ACE-I esp if microalbuminura or BP > mmHg systolic - Aspirin if C.V. risk 15% [ NZSSD C.V. Risk Assessment - ] 24

25 Insulin Start if: a) Lifestyle / oral agents maximised b) HbA1c on average in younger in older especially if symptomatic and if safe c) Consider earlier if GAD Ab +ve (ß cell function decreases faster) Perhaps earlier insulin protects remaining ß cells?? d) Severely symptomatic with HbA1c > 100mmol/mol even after diagnosis 25

26 Is insulin delayed too long? 26

27 Clinical Inertia in T2DM Management in Auckland Study of 2240 patients in 1 care in S.W. Auckland in on 2 oral agents: 954 (42.6%) of these had HbA1c 8% Nearly 2 year Later: 451 out of 605 patients with second HbA1c 8 were still not on insulin Targets reached more easily if not delayed Choe & Cutfield

28 DAWN Study Australian Results Anxieties about Diabetes (% of participants fully agree or mainly agree) Question: Please rate, on a 4-point scale, to what extent you agree with the following statements related to diabetes (fully disagree, mainly disagree, mainly agree, fully agree). I am very worried about the risk of hyopglycemic events I feel stressed because of my diabetes Type 1 diabetes Type 2 diabetes - on insulin Type 2 diabetes - no insulin I feel very anxious about my weight I am constantly afraid of my disease getting worse Peyrot M. et al. Diabetes Care : Rubin R. et al Diabetes Care : Practical Diab :

29 DAWN Study Australian Results Concerns about commencing insulin in people with Type 2 diabetes not treated with insulin (% fully agree or mainly agree) Questions: {Please rate, on a 4-point scale, to what extent you agree with the following statements related to diabetes (fully disagree, mainly disagree, mainly agree, fully agree)? I am very worried about having to start insulin Using insulin would help me manage my diabetes better Type 2 diabetes - no insulin Starting insulin would mean I had not followed my treatment recommendations properly Peyrot M. et al. Diabetes Care : Rubin R. et al Diabetes Care : Practical Diab :

30 Barriers to Insulin Patient: Fear of injections Perception of failure Social issues / employment Fear of complications (misinformation largely) Fear of hypos; weight gain Other priorities, esp if feeling well V Peragallo-Dittko. The Diab Ed. 2007, 33:606 30

31 Barriers to Insulin Doctor: Complexity of insulin regimens Experience / education / confidence Time / Resources / Costs Practice Nurse training / time Concerns re hypos / weight and poor compliance V Peragallo-Dittko. The Diab Ed. 2007, 33:606 31

32 Overcoming Barriers to Improved Diabetes Care and Insulin Use GP / Practice Nurse education with continued support from DN Specialist and/or Endocrinologist Practice Nurse / GP champions Regular update personal contact preferable Use diabetes clinics (know at least your local specialist nurse or endo) esp. community-based if needed. Funding: - Nurse clinics? - High needs patients Review diabetes patients in your practice see how they are doing discuss in forums together. 32

33 Overcoming Barriers to Insulin Marketing: Introduce concept of insulin deficiency early Modern insulin unlikely to cause significant hypo Weight gain minimised by continuing MET and lifestyle measures Use simple regimens to start with Use 4mm pen needles virtually painless plus latest pen devices Sell the benefits of improved glycaemic control including feeling better in many Importantly, tell the patient they are not failures for needing insulin Opportunistic injecting during consult 33

34 There are Many Ways to Start Insulin Difference between insulins are not large SO Be familiar with 1 or 2 insulins and keep it SIMPLE and SAFE 34

35 Insulins Available Covers Meals 1. Rapid Acting e.g. Humalog, Novorapid, Apidra 2. Intermediate Acting NPH Insulin e.g. Humulin NPH or Protaphane 3. Long Acting Basal e.g. Glargine (Lantus) 4. Premixed Insulins Good hr basal insulin Good hr basal insulin 25% Rapid 75% NPL Humalog Mix 25 50%Rapid 50% NPL Humalog Mix50 [ 30% Rapid 70% NPH Novomix 30 (soon to be available) ] 30% Regular 70% NPH Mixtard / Penmix 30/70 Heise t. et al. Diabetes Care :

36 Principles of starting insulin in Type 2 DM Education Review patients preferred food programme Look at glucose profiles to decide insulin type Continue METFORMIN and probably at first, sulphonylurea if using basal insulin Basal insulin to start with at lowish doses initially Patient learns to titrate insulin according to predefined B.G. target. 36

37 B.G. mmol/l B.G. Profile - Patient 1: On MET 850mg 1700mg : Gliclazide 160mg B.D. HbA1c 70mmol/mol BB BL BD 2hrs Post Dinner High fasting glucose ( hepatic glucose production overnight) 37

38 B.G. Profile - Patient 1: Start insulin with bedtime basal a) NPH e.g. Humulin NPH / Protaphane [See N.Z. Guidelines 2011] or possibly b) Lantus (glargine) 38

39 Basal Insulin can reduce Hyperglycaemia in T2D Hirsch et al, Diab Care;2005;23,2,

40 B.G. Profile - Patient 1: Continue MET / Reduce gliclazide to 80mg B.D. Use 8-10u insulin to start Pt can titrate by 2-3 units every 4-5 days till fasting glucose at 5-7mmol/L Frequent contact with practice nurse / G.P. initially 40

41 B.G. mmol/l B.G. Profile: If HbA1c not at target review B.G. profile including pre and 2 hrs post meal BB BL BD Here B.G. is drifting up in day despite noctural NPH Could: a) add B.D. NPH insulin, e.g. 8u am 10-12u evening or b) Lantus insulin once daily, e.g u nocte 41

42 B.G. mmol/l Patient 2: BB BL BD In this situation high levels (over 10) occur after breakfast and dinner especially. Consider short-acting insulin at dinner and breakfast as pre-mix, e.g. Humalog Mix 25 (25% Humalog 75% NPL) at breakfast and dinner at 8-10u BB 10-12U BD. 42

43 Pre-Mixed Insulins e.g. Humalog Mix 25; Penmix 30 Usually improves HbA1c after basal insulin alone, if moderate carbohydrate intake is eaten regularly Convenience with 1 injection at meal once or twice (usually) daily Post meal coverage but not flexible if carbohydrate intake at meals varies significantly 43

44 Other Insulin Regimens Lantus Plus 1 Lantus: Background insulin given morning or night with rapid acting insulin at biggest meal PLUS Humalog, Apidra or Novorapid 3-6u at largest meal then up titrate depending on 2hr postprandial test 44

45 Sequential Insulin Strategies in T2D ADA and EASD Guidelies for Type 2 DM

46 Elderly Individualise HbA1c target (less evidence-based advice) Treat if hyperglycaemic symptoms Beware nocturnal hypo, i.e. morning NPH may be best esp if lunch biggest meal. 46

47 Renal Failure Often need to reduce insulin requirements as egfr drops below 25-30ml/min Watch for hypos 47

48 When to Stop Orals Usually continue Metformin in Type 2 Stop sulphonylurea when prandial insulin started Usually stop pioglitazone when insulin is started (though pioglitazone may reduce insulin requirement in some) 48

49 Follow-Up after Insulin Start Frequent at start with phone / Most patients will progress to needing a short acting insulin so SMBG/HbA1c crucial to guide Diabetic Specialist Nurses will help at any stage Phone advice from Diabetes Specialist Insulin doses in overweight may easily exceed 1u/kg so important to regularly up titrate where necessary and review food and exercise regularly 49

50 Specialist Advice If concerns and especially If patient may have Type I: - Rapid weight loss - Leaner - +ve GAD Ab - If significant symptoms with significant hyperglycaemia e.g. HbA1c >100 at diagnosis may need insulin to start and/or 1-2 oral agents Young patient < 25 years Vocational drivers Recurrent hypos If significant micro or macrovascular complications 50

51 Conclusion Set HbA1c target and negotiate with patient Review lifestyle Follow clinical pathway for oral agents Start insulin early if not meeting HbA1c targets Keep it safe and simple Ask for help if needed Treat BP & lipids according to guidelines 51

52 Mandatory Product Information Humulin R, NPH, 30/70 and Humalog Insulin Lispro Solution, Mix25 and Mix50 are Prescription Medicines for the treatment of diabetes where insulin is required. Contain 100IU/mL of human insulin for injection or combinations as above. Humalog can be used in Continuous Subcutaneous Infusion Pumps. Humalog can be used in pregnancy. The safety and efficacy of Humalog Mix25 or Mix50 has not been established during pregnancy. Humulin R is a short-acting insulin. Humulin NPH and 30/70 are intermediate-acting insulins. Contraindications: hypoglycaemia. Apart from Humulin R do not give other Humulins intravenously. Administer subcutaneously. Transferring to another type or brand of insulin should be done under strict medical supervision. Adjustment of dose may be required in relation to animal source insulins. Insulin requirements may change significantly in thyroid, adrenal or pituitary disease and in presence of renal or hepatic disease. Insulin requirements may also increase during illness or emotional disturbance and dosage adjustment may be required with changes in diet or physical activity. Caution check with the patient if they are breast feeding and if they are on other prescription medicines. Common side effects are hypoglycaemia and resistance to insulin, allergic reactions at the site of injection such as redness, swelling or itching, muscle wasting and a general allergic reaction. Check carefully re prescribing the appropriate formulation. Full prescribing information can be found at These medicines are fully funded on the Pharmaceutical Benefit Schedule (Check Schedule for details). Eli Lilly & Company (NZ) Limited, Khyber Pass Road, Newmarket, Auckland. BYETTA approved Product Information. BYETTA is an UNFUNDED PRESCRIPTION MEDICINE used as adjunctive therapy for glycaemic control in type 2 diabetes mellitus with metformin, a sulphonylurea, or a combination with both, where adequate glycaemic control is no longer achieved. A prescription charge will apply. Do not use with end-stage renal disease, severe renal impairment. Not recommended in pregnancy or lactation. Caution: hypoglycaemia especially with sulphonylurea, severe gastrointestinal diseases, concurrent use with insulin, D-phenylalanine derivatives, meglitinides, alpha-glucosidase inhibitors, orlistat, opioids, and anticholinergics, thiazolidinedione, not a substitute for insulin, type 1 diabetes, diabetic ketoacidosis, concomitant use with medicines that affect renal function, hydration status, nausea, vomiting, diarrhoea, dehydration. Possible Side Effects: hypoglycaemia, nausea, vomiting, diarrhoea, feeling jittery, dizziness, headache, dyspepsia, injection-site reactions, abdominal distension, eructation, constipation, flatulence, dysgeusia. Use with caution with oral medications requiring rapid gastrointestinal absorption, medication associated with local gastrointestinal irritation e.g. bisphosphonates or tetracyclines, gastroresistant formulations e.g. proton pump inhibitors, oral contraceptives, oral antibiotics, warfarin. Contains 5μg or 10μg of exenatide for administration by subcutaneous injection, either twice daily, within 1 hour before the morning and evening meals, or 6 hours apart. Do not administer after a meal. Please review Data Sheet before prescribing. Full Data Sheet is available from Eli Lilly and Company (NZ) or check on Eli Lilly AUCKLAND. NZDBT